Toxicity and patient-reported outcomes of a phase 2 randomized trial of prostate and pelvic lymph node versus prostate only radiotherapy in advanced localised prostate cancer (PIVOTAL)

Purpose To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers. Methods and Materials In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity. Results One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group. Conclusions PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established

Optimal resolution tomography with error tracking and the structure of the crust and upper mantle beneath Ireland and Britain

The classical Backus–Gilbert method seeks localized Earth-structure averages at the shortest length scales possible, given a data set, data errors, and a threshold for acceptable model errors. The resolving length at a point is the width of the local averaging kernel, and the optimal averaging kernel is the narrowest one such that the model error is below a specified level. This approach is well suited for seismic tomography, which maps 3-D Earth structure using large sets of seismic measurements. The continual measurement-error decreases and data-redundancy increases have reduced the impact of random errors on tomographic models. Systematic errors, however, are resistant to data redundancy and their effect on the model is difficult to predict. Here, we develop a method for finding the optimal resolving length at every point, implementing it for surface-wave tomography. As in the Backus–Gilbert method, every solution at a point results from an entire-system inversion, and the model error is reduced by increasing the model-parameter averaging. The key advantage of our method stems from its direct, empirical evaluation of the posterior model error at a point. We first measure inter- station phase velocities at simultaneously recording station pairs and compute phase-velocity maps at densely, logarithmically spaced periods. Numerous versions of the maps with varying smoothness are then computed, ranging from very rough to very smooth. Phase-velocity curves extracted from the maps at every point can be inverted for shear-velocity (V S ) profiles. As we show, errors in these phase-velocity curves increase nearly monotonically with the map roughness. We evaluate the error by isolating the roughness of the phase-velocity curve that cannot be explained by any Earth structure and determine the optimal resolving length at a point such that the error of the local phase-velocity curve is below a threshold. A 3-D V S model is then computed by the inversion of the composite phase-velocity maps with an optimal resolution at every point. The estimated optimal resolution shows smooth lateral variations, confirming the robustness of the procedure. Importantly, the optimal resolving length does not scale with the density of the data coverage: some of the best-sampled locations display relatively low lateral resolution, probably due to systematic errors in the data. We apply the method to image the lithosphere and underlying mantle beneath Ireland and Britain. Our very large data set was created using new data from Ireland Array, the Irish National Seismic Network, the UK Seismograph Network and other deployments. A total of 11 238 inter-station dispersion curves, spanning a very broad total period range (4–500 s), yield unprecedented data coverage of the area and provide fine regional resolution from the crust to the deep asthenosphere. The lateral resolution of the 3-D model is computed explicitly and varies from 39 km in central Ireland to over 800 km at the edges of the area, where the data coverage declines. Our tomography reveals pronounced, previously unknown variations in the lithospheric thickness beneath Ireland and Britain, with implications for their Caledonian assembly and for the mechanisms of the British Tertiary Igneous Province magmatism

Overshadowing depends on cue and reinforcement sensitivity but not schizotypy

There is evidence for impaired selective learning mechanisms in individuals high in schizotypy. Overshadowing provides a direct test of selective learning based on cue salience and has previously been reported to be impaired in relation to schizotypy scores. The present study tested for overshadowing using food allergy and Lego construction task variants. Both variants used the same number of conditioned stimulus (CS) cues and the same number of learning trials. CS cues were trained in compound pairs or in isolation and overshadowing was subsequently tested on trials followed by negative versus positive outcomes. Participants also completed the O-LIFE to measure schizotypy and BIS-BAS scales to measure reinforcement sensitivity. Learning was demonstrated for both cue variants; however overshadowing emerged only in the Lego variant and only on the trials followed by the negative outcome. Contrary to expectations, there was no evidence for any relationship between overshadowing and O-LIFE scores. However, there was evidence of a positive relationship between overshadowing and BAS-Drive as well as a negative relationship with BIS-Anxiety, for the trials followed by the positive outcome in the food allergy variant. These results suggest that the development of overshadowing depends on cue and reinforcement sensitivity, but not necessarily on schizotypy

Neonatal infections: Case definition and guidelines for data collection, analysis, and presentation of immunisation safety data.

Maternal vaccination is an important area of research and requires appropriate and internationally comparable definitions and safety standards. The GAIA group, part of the Brighton Collaboration was created with the mandate of proposing standardised definitions applicable to maternal vaccine research. This study proposes international definitions for neonatal infections. The neonatal infections GAIA working group performed a literature review using Medline, EMBASE and the Cochrane collaboration and collected definitions in use in neonatal and public health networks. The common criteria derived from the extensive search formed the basis for a consensus process that resulted in three separate definitions for neonatal blood stream infections (BSI), meningitis and lower respiratory tract infections (LRTI). For each definition three levels of evidence are proposed to ensure the applicability of the definitions to different settings. Recommendations about data collection, analysis and presentation are presented and harmonized with the Brighton Collaboration and GAIA format and other existing international standards for study reporting

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth